I. Field of the Invention
The present invention deals generally with transdermal delivery of therapeutic agents by use of an applied electromotive force (emf), commonly known as iontophoresis. More particularly, the invention is directed to a system for iontophoresis that is self-contained, and quantitatively self-limiting. The system is contained preferably in a rather small skin-worn patch which contains electrodes and a therapeutic agent. When applied to the skin, the system completes a circuit and spontaneously initiates the flow of a galvanic current of measured, limited duration corresponding to the amount of therapeutic agent delivered. The system may be anode or cathode limited. The power source/dosage control systems are based on a galvanic couple power source selected from manufactured lots or batches of such power sources or source components of tested capacity so that each system capacity can also be designated on labels with a high degree of confidence. The system is self contained.
II. Related Art
The process of iontophoresis was described by LeDuc in 1908, and has since found commercial use in the delivery of ionically charged compounds such as pilocarpine, dexamethasone, and lidocaine. In this delivery method, ions bearing a positive charge are driven across the skin at the site of an electrolytic electrical system anode, while ions bearing a negative charge are driven across the skin at the site of an electrolytic electrical system cathode.
With iontophoretic devices, the application time and level of current flow (usually reported in units of milli-amp minutes) between the anode and cathode is directly correlated to the amount of drug delivered. The efficiency of drug delivery in an iontophoretic system can be measured by the proportion of current carried by the drug molecule, relative to the current carried by competing non-medication ions having the same charge as the medication.
At present, iontophoresis devices conventionally include two electrodes attached to a patient, each connected via a wire to a microprocessor-controlled electrical instrument. An illustration of a conventional iontophoretic system is shown in FIG. 1. Medication is placed under one or both of the electrodes for delivery into the body as the instrument is activated. The instrument is designed to regulate current flow and application time. Examples of such instruments are described in U.S. Pat. Nos. 5,254,081 and 5,431,625. Power for these devices is usually provided by DC batteries, which when providing power for the microprocessor-controlled circuitry allow application of a voltage to the electrodes to create a regulated current flow. The automated control of current flow and time (milliamp-minutes) is of great advantage in order to prevent excessive dosages of therapeutic agents from being delivered. However, these battery powered microprocessor-controlled systems are disadvantaged by the fact that patients are attached by wire to an instrument which limits patient mobility and ability to conduct normal daily activities. A typical application period is approximately 20 minutes to 2 hours, which consumes instrument, caregiver and patient time.
Such an early system is illustrated schematically in FIG. 1 which includes an instrument case 10 for containing a battery-powered current source, a microprocessor-controller, all necessary electronic circuitry and other controls (not shown). An output display is shown at 12. Positive and negative terminals 14 and 16 are connected respectively to external electrode systems 18 and 20 designed to be attached to the patient. Electrode 18 contains a buffer or salt solution at 22 and the electrode 20 is the working electrode containing the medication or therapeutic agent chamber at 24. At all times the patient must remain connected to the device 10 via electrode-connecting wires 26 and 28. All other necessary electronic circuitry for microprocessor-controlled current flow is contained in the instrument case 10.
More recently, wearable iontophoretic systems have been developed in which the electrical circuitry and power supplied are integrated into a single patch. These systems are advantageous in that they do not have external wires, and they are much smaller in size. Examples of such systems can be found in U.S. Pat. Nos. 5,358,483; 5,458,569; 5,466,217; 5,533,971; 5,605,536; and 5,651,768. However, these systems also have the drawback that they are relatively inflexible and expensive, owing to the multiple electronic components, battery power supplies and electrical interconnects.
U.S. Pat. No. 5,685,837 to Horstmann describes a wearable iontophoretic system, which can be designed to modulate current flow without use of microprocessor control In this design, each electrode consists of multi-layer sheet-like galvanic elements. Each sheet-like element incorporates a sandwiched electrolyte layer that collects oxidative and reductive byproducts. This does allow current flow to be regulated, e.g. gradually diminished, owing to the incorporation of very thin layers. The gradual current reduction follows a Nernstian defined voltage reduction from collection of byproducts in the electrolyte layer. The '837 invention is disadvantaged by 1) the need for a multi-layer electrode construction that can be challenging to manufacture and 2) a gradual, e.g. protracted, decrease in current where a more constant delivery rate, followed by an abrupt completion, would be desired.
Power to drive iontophoretic current flow can also be supplied by galvanic means, which utilizes dissimilar anode and cathode materials to produce a spontaneous current flow when they are contacted with the body. These systems hold the advantage that separate electrical circuitry and battery sources are not required. An iontophoretic device, not of the transdermal type, but one which utilizes galvanic means is described in U.S. Pat. No. 5,322,520. That system involves the use of two dissimilar galvanic materials in an implanted device or catheter system designed to deliver oligodynamic metal ions from its surface in order to kill bacteria on or near it. Yet another system for a urinary catheter is shown by DeLaurentis et al, in U.S. Pat. No. 5,295,979. These devices are disadvantaged by the fact that the amount of medication (active species) delivered is not automatically regulated and they require a timely removal of the device from the body to prevent a potentially toxic over-dosage of medication or excessive electrode by-product from being released. Still other galvanic battery patent examples are found in U.S. Pat. No. 5,162,042; UK 2,206,493; and UK 410,009.
A device disclosed by Muller et al in U.S. Pat. No. 5,320,731 uses an electrode consuming technique as a means to regulate dosage without the need to incorporate a microprocessor. In the '731 system, electrodes are described which are consumed as current flows and are designed in a manner where consumption of the electrode is complete at the desired delivery dosage. However, this invention requires an external connected power source and means to monitor voltage, therefore advantage is limited.
Additionally, while prior art galvanic devices may have a “maximum” delivery capacity as defined by an amount of active materials incorporated within, the “actual” delivered capacities will vary (and in fact therefore be “unknown”) owing, for example, to unpredictable breaks in electrical contact prior to full consumption of active materials, and/or corrosive side reactions which will consume active material without providing iontophoretic current. Other reasons for inaccuracies in predictability appear below.
From the above, it will be appreciated that a simplified skin-patch-type system for iontophoresis that is self-contained, inexpensive and relatively simple with respect to electrical aspects, particularly one which further controls the amount of therapeutic agent to be delivered would be in great demand.
Accordingly, an advantage of the present invention is the provision of a self-contained, self-limiting transdermal iontophoretic drug delivery device. The present invention provides such a device which is galvanically powered and does not require any separate current source or electric circuitry including an embodiment in the form of a thin planar, conforming, and relatively small iontophoretic wearable skin patch-type device which does not interfere with the daily activities of the wearer.
The present invention provides a wearable galvanic iontophoresing device that is designed to deliver a controlled dosage of medication in an automated fashion, based on a more reliable, test-verified galvanic charge capacity in the corresponding power source. Provision can be made to eliminate oxygen reduction current and associated pH change in the system. Both techniques act to prevent an over-dosage of medication or excessive release of electrode by-product materials.
A method for delivering a controlled dosage at a controlled rate of medication iontophoretically in an automated fashion entirely dependent on a self-contained skin-patch device is also provided.
Other advantages of the invention will become apparent to those skilled in the art upon further familiarization with the specification, drawings and claims herein.